BIOCHEMICAL EVALUATION OF AMINERGIC FUNCTION DURING RESPONSES TO STRESS & DISEASE

应激反应过程中胺能功能的生化评估

• 批准号: 3860836
• 负责人: I J KOPIN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3860836
• 关键词: 3,4 dihydroxyphenylacetate; Parkinson's disease; autonomic disorder; catecholamines; dihydroxyphenylalanine; dihydroxypropoxymethylguanine; dopamine; epinephrine; excretion; human tissue; hypertension; hypothalamus; laboratory rat; microdialysis; neuropharmacology; neurophysiology; neurotransmitter metabolism; norepinephrine; physiologic stressor; plasma; psychological stressor; stress; sympathetic nervous system; tyrosine 3 monooxygenase; urinalysis

The main objectives of this project are (1) to determine the physiologic significance of alterations in plasma levels and urinary excretion rates of the catecholamines, their metabolites and their precursor, DOPA; (2) to develop in animals and humans clinically useful methods for assessing catecholaminergic function; and (3) to apply these methods to examine function of catecholaminergic neurons in the peripheral sympathetic nervous system and in brain. Changes in tissue or plasma levels or urinary excretion rates of catecholamines and their metabolites, and tissue tyrosine hydroxylase levels are evaluated, during and after stress, in response to pharmacologic treatments, or in disease states in animals, in normal subjects, and in patients with various neurologic or related disorders (autonomic dysfunction, Parkinson's disease, hypertension, etc). in rats, plasma levels of DOPA parallel pharmacologic or stress-induced enhancement of norepinephrine release, even after adrenalmedullectomy. Tyrosine hydroxylase levels in tissues do not reflect the rate of catecholamine production, indicating that tyrosine hydroxylation can be regulated independently of the levels of tyrosine hydroxylase. Plasma levels of DOPAC, the deamination product of dopamine and HVA, its O-methylated derivative, increase under conditions in which norepinephrine is released. This occurs also in the central nervous system, as indicated by experiments in which microdialysates are obtained from specific nuclei in rat brain hypothalamus. Inhibitors of tyrosine hydroxylase or ganglionic blockade with chlorisondamine prevent stress-induced elevations of DOPA, dopamine and norepinephrine and their metabolites in plasma. Increments in plasma levels of DOPA and DOPAC reflect rates of tyrosine hydroxylation, mostly in peripheral sympathetic neurons. Most patients with pure autonomic failure were found to have low plasma levels of DOPA, norepinephrine, DHPG and DOPAC, consistent with loss of peripheral sympathetic neurons, whereas in most patients with multiple system atrophy, levels of DOPA, DHPG and DOPAC are generally normal; this is consistent with normal catecholamine biosynthesis in these patients who are believed to have intact peripheral sympathetic neurons but diminished nerve impulse traffic from the central nervous system.

本项目的主要目的是（1）确定生理 血浆水平和尿排泄率变化的意义 儿茶酚胺、其代谢物及其前体多巴;（2） 在动物和人类中开发临床上有用的方法， 儿茶酚胺能功能;（3）应用这些方法检查 外周交感神经中儿茶酚胺能神经元的功能 神经系统和大脑。 组织或血浆水平变化，或 儿茶酚胺及其代谢物的尿排泄率，以及 组织酪氨酸羟化酶水平在评估期间和之后， 压力，对药物治疗的反应，或在疾病状态下， 动物，在正常受试者，并在各种神经或 相关疾病（自主神经功能障碍，帕金森病， 高血压等）。 在大鼠中，多巴的血浆水平与药理学或应激诱导的 增强去甲肾上腺素释放，即使在肾上腺髓质切除术后。 组织中的酪氨酸羟化酶水平不能反映 儿茶酚胺的生产，表明酪氨酸羟基化可以 独立于酪氨酸羟化酶的水平调节。 血浆 DOPAC的水平，多巴胺和HVA的脱氨基产物， O-甲基化衍生物，在其中 释放去甲肾上腺素。 这也发生在中枢神经系统中。 系统，如获得微透析液的实验所示 来自大鼠大脑下丘脑的特定核团。 酪氨酸抑制剂 羟化酶或神经节阻滞剂 应激诱导的多巴、多巴胺和去甲肾上腺素升高及其 血浆中的代谢物。 DOPA和DOPAC的血浆水平增加 反映酪氨酸羟化率，主要是在外周交感神经 神经元 大多数单纯性自主神经功能衰竭的患者， DOPA、去甲肾上腺素、DHPG和DOPAC的水平，与 外周交感神经元，而在大多数患者中， 系统萎缩，DOPA，DHPG和DOPAC水平通常正常;这 与这些患者中正常的儿茶酚胺生物合成一致 他们被认为有完整的外周交感神经元， 中枢神经系统的神经冲动减少